ROLE OF CYTOSKELETAL STRUCTURE IN MODULATION OF INTESTINAL PERMEABILITY

The intestine contains the largest interface between man and his environment; thus, the intestinal barrier could be a key factor in health and disease states. This barrier is a highly selective gatekeeper that permits the passage of nutrients and prevents the penetration of harmful bacterial products and dietary antigens. The intestinal barrier is composed of immunological and nonimmunological compartments and the latter part is made up of multilayered structural and functional components. The intestinal epithelium and its paracellular tight junctions appear to be the key for integrity of this barrier. The cytoskeletal assembly is essential for maintaining epithelial structure, transport, and functional integrity, but is also pivotal for integrity of the paracellular pathway, especially the tight junction complex. Actin and microtubules are two cytoskeletal filaments that play key roles in regulation and maintenance of the intestinal barrier. Various noxious agents such as ethanol and/or oxidants can induce cytoskeletal damage and disruption of barrier integrity. The injurious effects of these compounds are mediated through upregulation and activation of inducible nitric oxide synthase (iNOS) and the resultant NO overproduction and nitration and oxidation of actin and tubulin. Oxidized cytoskeletal proteins result in depolymerization of cytoskeletal filaments, cytoskeletal disassembly and disarray and eventually disruption of barrier function. The disrupted barrier can initiate or perpetuate an inflammatory cascade that will result in intestinal mucosal injury and inflammatory bowel disease flare-up. There are several lines of repair/defense that help to brake this inflammatory cascade, reestablish barrier integrity and thus limit or terminate mucosal injury. One of these lines of defense is mediated through protecting factors such as epidermal growth factor, which prevents ethanol-induced and oxidative damage to the gastrointestinal epithelium.